Localisation of intrahepatic interleukin 6 in patients with acute and chronic liver disease.

Abnormal cytokine levels have been described in patients with chronic liver disease, but studies correlating cytokine homeostasis with abnormalities in coagulation and fibrinolysis are lacking. In order to establish a link between cytokines and the hemostatic changes the following parameters were determined in 44 patients with cirrhosis (alcoholic =15, postnecrotic = 22, others = 7): TNF-α, IL·6, thrombin-antithrombin (TAT) complexes, prothrombin fragment 1 + 2 (F1 + 2) and t-PA by using enzyme-linked immunosorbent assays, and PAI-1, plasminogen and α₂-antiplasmin (α₂-AP) by using chromogenic substrates. All patients were at stages B and C of Child’s classification when entering the study. Mean cytokine concentrations were significantly higher in cirrhotic patients as compared to age- and sex-matched controls (p < 0.009). There was a significant increase of TAT (p < 0.02) and F1 + 2 (p < 0.001) in the patients groups, suggesting a grade of intravascular coagulation. A hyperfibrinolytic state as demonstrated by an increase of t-PA and decrease of plasminogen and α₂-AP was also observed (p < 0.001). We could define a subgroup of patients with cytokine values higher than 20 pg/ml. Interestingly, in this group there was a significant increase of TAT (p < 0.04) and t-PA (p < 0.02) levels and a decrease of plasminogen and α₂-AP (p < 0.02) as compared to values observed in patients with cytokines lower than 20 pg/ml. We conclude that high levels of TNF-α and IL-6 may contribute to hyperfibrinolysis and intravascular coagulation in patients with liver cirrhosis, as assessed by the increase of TAT and t-PA levels and the reduction of plasminogen and α₂-AP.

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“…The observed increase was not related to the etiology of the process, as has been re ported previously [13].…”

Section: Discussionsupporting

confidence: 60%

Increased Concentrations of Tumor Necrosis Factor and lnterleukin-6 Contribute to the Hemostatic Abnormalities in Advanced Liver Disease

Páramo

Sangro²,

Prosper³

et al. 1995

Pathophysiol Haemos Thromb

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“…In humans, IL-6 is produced within the liver by Kupffer's cells and other antigen-presenting cells, endothelial cells, 11 and BEC 8 during acute and chronic hepatitis, alcoholic liver disease, 11 PBC, PSC, and other causes of cirrhosis. 8,13 During stage I-III primary biliary cirrhosis there is significant liver enlargement, which is associated with elevated intrahepatic IL-6 mRNA levels 12 and a high rate of hepatocyte proliferation.…”

Section: Discussionmentioning

confidence: 99%

The Development and Compensation of Biliary Cirrhosis in Interleukin-6-Deficient Mice

Ezure

Sakamoto

Tsuji

et al. 2000

The American Journal of Pathology

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In an effort to understand the role of IL-6/gp130 signaling in chronic liver injury, IL-6 deficient (IL-6 ؊/؊ ) and wild-type control (IL-6 ؉/؉ ) mice were subjected to bile duct ligation (BDL) for 12 weeks. This maneuver causes chronic biomechanical stress and liver injury, fueling sustained biliary epithelial and hepatocyte proliferation. By 12 weeks after BDL, IL-6 ؊/؊ mice develop significantly higher total serum bilirubin levels (23.2 ؎ 2.3 versus 14.9 ؎ 2.1 mg/dl, P < 0.0001; delta bilirubin subfraction 16.7 ؎ 4.0% versus 9.2 ؎ 1.8%; P < 0.002), and the majority (15/18) show "black" gallbladder bile, compared to IL-6 ؉/؉ mice (5/16; P < 0.003). The IL-6 ؊/؊ mice also cannot sustain the compensatory liver mass increase commonly seen with chronic obstructive cholangiopathy, because of less hepatocyte proliferation, despite a rate of hepatocyte apoptosis similar to that of IL-6 ؉/؉ mice. Moreover, IL-6 ؊/؊ mice show a more advanced stage of biliary fibrosis and a higher mortality rate than the IL-6 ؉/؉ controls (51% versus 23%; P < 0.02). These phenotypic changes in the IL-6 ؊/؊ mice are associated with decreased expression and phosphorylation of gp130 and the transcription factor STAT3, compared to IL-6 ؉/؉ mice. Daily treatment with exogenous recombinant IL-6 for 3-6 weeks starting at 6 weeks after BDL significantly lowers the serum total bilirubin in both groups. In the IL-6 ؊/؊ mice, exogenous IL-6 treatment also increases the level of gp130 protein expression and completely reverses the loss of liver mass by increasing the hepatocyte proliferation. In conclusion, IL-6 appears to contribute to biliary tree integrity and maintenance of hepatocyte mass during chronic injury. Interleukin-6 (IL-6)/gp-130 signaling is involved acutely in hepatocyte 1,2 and biliary epithelial cell (BEC) growth control and pathobiology. For example, liver regeneration after partial hepatectomy (PH) is delayed in IL-6 Ϫ/Ϫ mice, 1,2 whereas IL-6/sIL-6R double transgenic mice develop hepatocellular hyperplasia and adenomas. 3 Although data on the in vitro effects of IL-6 on hepatocyte proliferation are conflicting, 4,5 there are at least two mechanisms by which IL-6/gp-130 promotes BEC growth in vitro. IL-6 is able to directly stimulate BEC DNA synthesis 6 and inhibit apoptosis, via an increase of the bcl-2/ bax ratio. 7 When stimulated by other proinflammatory cytokines or phorbol esters, nonneoplastic BEC can also produce and secrete IL-6, which can then act as an autocrine growth factor under conditions of BEC stress. 6,8,9 Serum and liver IL-6 levels are also elevated in patients with chronic inflammatory liver diseases. 10 -13 In this setting, IL-6 has traditionally been considered to exert a profibrogenic and mitoinhibitory influence on the development of cirrhosis. 10,14 -17 However, in other "chronic inflammatory proliferative disorders," such as psoriasis and rheumatoid arthritis, IL-6 has been linked with keratinocyte and synovial cell proliferation, respectively. 18 In addition, recent studies have shown that gp130 sign...

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“…IL-4 can promote the production of anti-HBV neutralizing antibodies and help in the clearance of circulating virus (20,21). In contrast, IL-6 and IL-10 are involved in the pathogenesis of CHB (20,21,45 T cells in CHB patients were significantly lower than those in the HC. These data suggest that although CHB patients had a greater number of CD4 ϩ T cells, they had an impairment in CD4 ϩ T cell function.…”

Section: Discussionmentioning

confidence: 79%

Treatment with Telbivudine Positively Regulates Antiviral Immune Profiles in Chinese Patients with Chronic Hepatitis B

Cai

et al. 2013

Antimicrob Agents Chemother

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dChronic infection with hepatitis B virus (HBV) is associated with impairment of T and NK cell immunity. This study was aimed at investigating the impact of treatment with telbivudine (LDT) on T and NK cell immunity in patients with chronic hepatitis B (CHB). A total of 54 CHB patients and 30 healthy controls (HC) were recruited. Individual patients were treated orally with 600 mg LDT daily for 13 months. The serum HBV DNA loads, the levels of the HBV-related biomarkers alanine aminotransferase (ALT) and aspartate transaminase (AST), and the numbers of different subsets of peripheral T and NK cells in subjects were measured before and longitudinally after LDT treatment. Following treatment with LDT, the serum HBV DNA loads and the percentages of HBsAg-or HBeAg-seropositive cases were gradually reduced, accompanied by decreased levels of serum ALT

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Localisation of intrahepatic interleukin 6 in patients with acute and chronic liver disease.

Cited by 39 publications

References 22 publications

Increased Concentrations of Tumor Necrosis Factor and lnterleukin-6 Contribute to the Hemostatic Abnormalities in Advanced Liver Disease

Increased Concentrations of Tumor Necrosis Factor and lnterleukin-6 Contribute to the Hemostatic Abnormalities in Advanced Liver Disease

The Development and Compensation of Biliary Cirrhosis in Interleukin-6-Deficient Mice

Treatment with Telbivudine Positively Regulates Antiviral Immune Profiles in Chinese Patients with Chronic Hepatitis B

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